Clinical depression is a neurological disorder that affects a steadily increasing number of the population. Currently, two generations of antidepressants are utilized by physicians. The discovery of the tricyclic antidepressants (TCA) and the monoamine oxidase inhibitors were the first generation of antidepressants. Although these represented a radical approach to the therapy of depression, TCA and monoamine oxidase inhibitors suffer from serious side effects and toxicity in overdose. As a result, a second generation of antidepressants with an improved safety profile were developed, for example, the selective serotonin reuptake inhibitors (SSRI), reversible monoamine oxidase inhibitors, and other compounds with different mechanisms of action, like bupropion, nefazodone and venlafaxine. These antidepressants are largely devoid of anticholinergic and cardiovascular side effects. However, they do not exhibit a broader efficacy over TCAs, and SSRIs are less effective in severe forms of depression and lose efficacy over time. A further disadvantage of nearly all currently used antidepressants is their slow onset of action. In general, antidepressants require several weeks (2-6 weeks) of continuous administration before their mood elevating properties become manifest. Currently, no antidepressants with an efficacy >70% and a fast onset of action (<2-3 weeks) are available.
The monoamine theory of depression still remains the prevailing basis for the design of safer and more potent antidepressants. This theory postulates that the illness arises as a consequence of a defect in the synaptic availability of monoamines, particularly serotonin and norepinephrine. While not wishing to be bound to any particular theory, it is believed that administration of antidepressants blocks uptake of such monoamines and increases the amount of neurotransmitters in the synaptic cleft and therefore enhances their availability at pre- and postsynaptic receptors. However, mood-elevating effects are usually first observed after several weeks of administration. This is probably due to adaptive changes in receptor sensitivity and density in both the serotonin and norepinephrine circuitry. Additionally, there is growing evidence that several receptors, apart from the reuptake sites, mediate antidepressive responses. Thus, it is believed that the 2, , 5-HT1A, 5-HT2A and D2 receptors contribute to the efficacy and, particularly, to a rapid onset of antidepressant action.
More generally, it is also believed that the onset of other conditions, including, but not limited to, neurodegenerative diseases (Parkinson's Disease and Alzheimer's Disease), substance addiction (e.g., cocaine addiction), Attention Deficit Disorder (ADD), and bipolar disorder, involve a defect in monoaminergic neurotransmission. Thus, the ability to block monoamine transporters (and thus block the reuptake of monoamines), and thus effect an increase in concentration of monoamines more safely and efficiently, would be useful in the treatment of any condition caused by a deficiency in monoamine concentration.
Clearly, there remains a need to develop therapeutics for the treatment of conditions caused by a deficiency in monoamine concentration, preferably for the treatment of depression, that are broadly efficacious, safe (e.g., have fewer side effects associated with them), and have a fast onset of action. Additionally, because of the role that other mechanisms and systems may play in the therapeutic response, it would be ideal to develop a class of therapeutics capable of acting at more than one target site.